The present invention relates to the use of amides of xcex3-hydroxybutyric acid, herein referred to as GHB, in the treatment of drug addiction, such as heroine, cocaine and, in particular, in the treatment of alcoholism, and more particularly in reducing chronic alcoholics desire for and habit of consuming alcoholic drinks and in the treatment of abstinence syndrome.
The salts of 4-hydroxybutyric acid, e.g. the sodium salt, proved to be effective both in the treatment of the syndrome of abstinence from alcohol and in reducing the desire for and addiction to alcohol in alcoholic patients and disclosed in EP-A-344,704 and in the treatment of drug addiction, as reported in WO 93/00083. One of the advantages of said salts is that they do not cause the inconveniences of Disulfiram (Antabuse(copyright)), a drug having several untoward effects, such as for example the symptoms known as the xe2x80x9cacetaldehyde syndromexe2x80x9d, which may also result in fatality.
The sodium salt of GHB is absorbed very quickly by the gastroenteric apparatus with a maximum concentration peak already at about 35-40 min after administration. However, it presents a half-life time of about 20-25 min, its elimination from the body being rather quick [EP-A-635,265].
In view of the foregoing, to secure a satisfactory pharmacological cover in patients having a craving for alcohol, especially in the early time of treatment, GHB sodium salt has to be administered several times a day, in particular at least 4 times a day.
Therefore, the need for new drugs, active in the treatment of alcoholism, capable of improving the pharmacokinetic aspects of sodium xcex3-hydroxybutyrate, is deeply felt.
U.S. Pat. No. 4,195,096 discloses N-chlorobenzyl-, N-fluorobenzyl- and N-alkyl amides of xcex3-hydroxybutyric acid as fungicides for plants.
U.S. Pat. No. 3,940,258 describes the use, as aquatic herbicides, of N-phenylalkylamides and in particular the N-benzylamides of GBH, optionally substituted on the phenyl group with methyl or halo groups, useful also as thickeners for lubricants and paints.
N-alkylenebenzoxazinoamides of GHB showing anti-MAO activity are known [J. Heterocyclic Chem., 1983, 20(1), 139-144]. GHB acid amides useful as inflammation and/or allergy inhibitors are N-alkylenebenzenamides of GHB substituted on the benzene ring with alkylene, alkenyl, and alkyleneoxy residues containing hydroxyl groups (Chemical Abstracts, Vol. 112, 1990: CA 112: 55263z relating to JP 01,121,255 [89,121,255]) and an N-alkylenecycloalkylamide of GHB acid described in Chemical Abstracts, Vol. 118, CA 118: 1011592xe2x80x94Eur. J. Med. Chem., 1992, 27 (6), 595-610. U.S. Pat. Nos. 2,773,062 and 2,849,455 describe N-xcex1-ethyl-piperonyl ethers of N-benzyl, N-furfuryl, and N-tetrahydrofurfuryl amides of GHB showing insecticidal activity.
Up to the present time no biological activity has been described for the 0-acyl derivatives of GHB amides, such as for example the benzoyl esters of GHB N-benzylamides, useful as components of thermosensitive coating materials [Chemical Abstracts, CA 116: 140229; data base abstract referred to JP 3,240,588].
A pharmacological activity has been attributed to imidazoquinolinone-etherified GHB amides, e.g. they are blood-platelet-antiaggregating agents, antiinflammatory agents and/or antithrombotics [Drug Des. Discovery, 1955, 12(3), 249-258].
Chemical Abstract: CA 122:105695 referred to USP 957491 describes the carbostyriloxytocin receptor antagonist activity and the use of GHB carbostyril N-benzylamides as vasodilators and antihypertensives.
Chemical Abstract, Vol. 110, 1989, CA 110: 135655c, referred to EP-A-257,378, describes the antiviral activity of halo-phenyl ethers of a nucleosidic alkylene-pyrimidine amide of GHB.
The body growth stimulation properties of phenoxyamides, e.g. of N-benzylamide of a chlorophenyl ether of GHB, and their use as animal feed additives, have also
The body growth stimulation properties of phenoxyamides, e.g. of N-benzylamide of a chlorophenyl ether of GHB, and their use as animal feed additives, have also been described [Chemical Abstract, Vol. 104, 1986, p. 607, CA 104:186147xxe2x80x94DD 161,247].
The applicant has now unexpectedly found that the amides of xcex3-hydroxybutyric (GHB) acid show a neuropharmacological activity qualitatively comparable to or exceeding that of GHB. If compared to GHB they cause excitatory effects at lower doses and/or of longer duration. Therefore, said amides are useful in the treatment of drug addictions, such as heroin, cocaine and, in particular, in the treatment of alcoholism, and more particularly in reducing chronic alcoholics desire for and habit of consuming alcoholic drinks and in the treatment of abstinence syndrome.
The present invention relates to the use of amides of formula (I) 
where
R1 is a mono- or polycyclic aromatic group, containing one or more carbocyclic or heterocyclic aromatic rings or mixtures thereof, having 5 to 7 atoms in the ring, said rings being optionally substituted with one or more groups selected from C1-C8 alkyl, C1-C8 alkoxyl, one or more aminic monoalkylaminic, dialkyl aminic groups and halogen, where said C1-C8 alkyl and alkoxyl groups may contain or be substituted with one or more double or triple bonds, or with one or more halogen groups and said mono or dialkyl aminic group typically having from 1 to 8 carbon atoms;
R2 is selected from H; a linear or branched alkyl, typically having 1 to 6 carbon atoms; a linear or branched alkyl substituted with one or more double or triple bonds, or with one or more aromatic groups, typically having 1 to 6 carbon atoms;
Q is selected from H and a linear or branched alkyl having 1 to 6 carbon atoms;
n is an integer from 1 to 4;
T1 and T2, individually, are selected from H and a linear or branched alkyl having 1 to 6 carbon atoms,
The aforesaid amides are e.g. useful in the treatment of alcoholism, and more in particular in reducing the voluntary consumption of ethyl alcohol in alcoholic patients and in the treatment of the abstinence syndrome.
The aforesaid amides are also useful in the treatment of the crises of abstinence from habit-forming drugs, such as heroin, morphine, cocaine, and psychoactive drugs, which are originated from the same biochemical mechanisms as those responsible for the crises of abstinence from alcohol. To the best of the applicant""s knowledge, pharmaceutical compositions containing a therapeutically effective dose of at least an amide of formula (I), in which R1, Q, T1, T2 and n are as defined above, and R2 is selected from the group consisting of H; a linear or branched alkyl, typically having 1 to 6 carbon atoms; a linear or branched alkyl substituted with one or more double or triple bonds or with one or more aromatic groups, typically having 1 to 6 carbon atoms; in combination with one or more pharmaceutically acceptable excipients and/or diluents, have not been described up to the present time.
To the best of the applicant""s knowledge, the following amides, the pharmaceutical compositions containing same, and the preparation procedure thereof, have not been described up to the present time and, therefore, constitute further features of the present invention:
a) amides of formula (1), in which R1, Q, T1, T2 and n are as defined above for formula (1), and R2 is selected from the group consisting of a linear or branched alkyl, typically C1-C6; a linear or branched alkyl, typically C1-C6, substituted with one or more double or triple bonds or with one or more aromatic groups;
b) amides of formula (I), in which R1, is an aromatic heterocycle, Q, T1, T2 and n are as defined above for formula (I), and R2 is as defined above for formula (i), provided it is different from an aromatic group, and more particularly R2 is H;
c) amides of formula (i), in which 0 is a C1-C6 alkyl, and R1, R2, T1, T2 and n are as defined above for formula (I).
The present invention also relates to the single compounds listed hereinafter, herein referred to as compounds 2), 3), 7) 8), 9), 10), 11), 12), 13), 14)15), 16), 19) (and relevant pharmaceutical compositions and preparation procedure), which, to the applicant""s knowledge, are not known to the art [compounds 7), 10), 11), 12), 13), 14), 15), 19) belong to the amides of group a); compound 9) to group b); compound 16) to group c)].
The applicant has also found that the amides of formula (I), in which R2 is alkyl, typically a C,-C3 alkyl, such as methyl, ethyl, and propyl, may be conveniently prepared through the steps of:
a) treating xcex3-butyrolactone with an alcohol of formula
R2OHxe2x80x83xe2x80x83(III) 
in which R2 is an alkyl (preferably Cl-C3), in the presence of an ortho-formiate of formula (IV)
Hxe2x80x94C(OR2)3xe2x80x83xe2x80x83(IV) 
in which R2 is as defined above for the alcohol of formula (III), in the presence of an acid catalyst, to give an ester of formula (V)
R2Oxe2x80x94(CH2)3xe2x80x94COOR2xe2x80x83xe2x80x83(V) 
in which R2 is as defined above for the alcohol of formula (III);
b) treating the ester of formula (V) obtained in a) with an amine of formula (VI) 
where R1, Q, T1, T2, and n are as defined above for formula (I), in the presence of an ammonium halide